title: Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer.
abstract: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Mitochondrial dysfunction has been postulated to render cancer cells resistant to apoptosis based on the Warburg hypothesis. However, few studies have investigated the prognostic value of mitochondrial DNA (mtDNA) content and G10398A polymorphism in NSCLC patients. mtDNA copy number and G10398A polymorphism in 128 NSCLC tissue samples were assessed by real-time PCR (RT-PCR) and PCR-RFLP respectively, and their relationship to prognosis were analyzed by survival analysis and Cox proportional hazards model. In vitro, an mtDNA deletion A549 ρ(0) cell model was utilized to assess the function of mtDNA on radiosensitivity. Cell cycle distribution and reactive oxygen species (ROS) were analyzed to elucidate the potential mechanisms. For the whole group, the median follow-up time and overall survival time were 22.5 and 23.4 months, respectively. Patients with high mtDNA content had a marginally longer survival time than patients with low mtDNA content (P=0.053). Moreover, patients with high mtDNA content plus 10398G had a significantly longer overall survival time compared with those having low mtDNA content plus 10398A (47 vs. 27 months, P<0.05). In addition, multivariate analysis showed that stage and low mtDNA content plus 10398A were the two most independent prognostic factors. In vitro, the A549 ρ(0) cells showed more resistance to radiation than ρ(+) cells. Following radiation, ρ(0) cells showed delayed G2 arrest and lower ROS level as compared to ρ(+) cells. In conclusion, the present study suggests that in patients with NSCLC, low mtDNA content plus 10398A could be a marker of poor prognosis which is associated with resistance to anticancer treatment caused by low mtDNA content plus 10398A polymorphism resulting in mitochondrial dysfunction.
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang, Wuhan, Hubei 430071, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Huan-Gang
authors.initials: HG
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Peng
authors.forename: Yue-Hua
authors.initials: YH
authors.lastname: Wei
authors.forename: Jing-Ni
authors.initials: JN
authors.lastname: Wei
authors.forename: Cong-Hua
authors.initials: CH
authors.lastname: Xie
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.forename: Ya-Hua
authors.initials: YH
authors.lastname: Zhong
authors.forename: Gong
authors.initials: G
authors.lastname: Zhang
authors.forename: Di
authors.initials: D
authors.lastname: Deng
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Zhou
authors.forename: Fu-Xiang
authors.initials: FX
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology*; D011110:Polymorphism, Genetic; D011379:Prognosis; D016016:Proportional Hazards Models; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; C512478:EGFR protein, human; D066246:ErbB Receptors